Persistent
pruritus is a common disabling dermatologic symptom associated with different etiologic factors. These include primary skin conditions, as well as neuropathic, psychogenic, or systemic disorders like chronic
liver disease. Defective clearance of potential pruritogenic substances that activate itch-specific neurons innervating the skin is thought to contribute to cholestatic
pruritus. However, because the underlying disease-specific pruritogens and itch-specific neuronal pathways and mechanism(s) are unknown, symptomatic therapeutic intervention often leads to no or only limited success. In the current study, we aimed to first validate rats with bile duct
ligation (BDL) as a model for hepatic
pruritus and then to evaluate the contribution of
inflammation, peripheral neuronal sensitization, and specific signaling pathways and subpopulations of itch-responsive neurons to scratching behavior and thermal
hypersensitivity. Chronic BDL rats displayed enhanced scratching behavior and
thermal hyperalgesia indicative of peripheral
neuroinflammation. BDL-induced itch and
hypersensitivity involved a minor contribution of histaminergic/serotonergic receptors, but significant activation of
protein-activated receptor 2 (PAR2)
receptors, prostaglandin PGE2 formation, and potentiation of transient receptor potential vanilloid 1 (TRPV1) channel activity. The sensitization of dorsal root ganglion nociceptors in BDL rats was associated with increased surface expression of PAR2 and TRPV1
proteins and an increase in the number of PAR2- and TRPV1-expressing peptidergic neurons together with a shift of
TRPV1 receptor expression to medium sized dorsal root ganglion neurons. These results suggest that
pruritus and
hyperalgesia in chronic cholestatic BDL rats are associated with
neuroinflammation and involve PAR2-induced TRPV1 sensitization. Thus, pharmacological modulation of PAR2 and/or TRPV1 may be a valuable therapeutic approach for patients with chronic liver
pruritus refractory to conventional treatments.